MARAN NethMap Consumption of antimicrobial agents and antimicrobial resistance among medically important bacteria in the Netherlands

Transcription

1 NethMap 215 Consumption of antimicrobial agents and antimicrobial resistance among medically important bacteria in the Netherlands MARAN 215 Monitoring of Antimicrobial Resistance and Antibiotic Usage in Animals in the Netherlands in 214 Autoriteit Diergeneesmiddelen Autoriteit Diergeneesmiddelen Autoriteit Diergeneesmiddelen

2 Part 1: NethMap 215 pg Part 2: MARAN 215 pg 1-72

3 NethMap 215 Consumption of antimicrobial agents and antimicrobial resistance among medically important bacteria in The Netherlands in 214 June 215

4 Colophon This report is published under the acronym NethMap by the SWAB, the Dutch Foundation of the Working Party on Antibiotic Policy, in collaboration with the Centre for Infectious disease control (CIb) of the RIVM, the National Institute for Public Health and the Environment of the Netherlands. SWAB is fully supported by a structural grant from CIb, on behalf of the Ministry of Health, Welfare and Sports of the Netherlands. The information presented in NethMap is based on data from ongoing surveillance systems on the use of antimicrobial agents in human medicine and on the prevalence of resistance to relevant antimicrobial agents among medically important bacteria isolated from healthy individuals and patients in the community and from hospitalized patients. The document was produced on behalf of the SWAB by the Studio of the RIVM. NethMap can be ordered from the SWAB secretariat, c/o Secretariaat SWAB p/a Postbus 39, 5854 ZG Bergen (L) or by to secretariaat@swab.nl. NethMap 214 and earlier versions are also available from the website of the SWAB: Contents may be reproduced in publications (book chapters, papers, reviews, and slide reviews etcetera) without permission with a maximum limit of four figures and/or tables per publication and full credit (reference) to the original publication. Editors Dr Ir SC de Greeff Prof Dr JW Mouton Section Editors Dr T Leenstra Dr DC Melles Prof Dr DJ Mevius Dr S Natsch Board-members of SWAB Prof Dr JW Mouton (chair) Dr WJ Wiersinga (treasurer) Dr PD van der Linden (secretary) Dr MP Bauer Prof Dr AW Friedrich Prof Dr BJ Kullberg Dr DC Melles Dr S Natsch Dr JWPM Overdiek Prof Dr JM Prins Prof Dr AMGA de Smet Prof Dr DJ Touw Prof Dr A Verbon Dr CM Verduin Prof Dr ThJM Verheij Prof Dr JA Wagenaar Dr T Wolfs Members of SWAB s working group on surveillance of antimicrobial resistance Dr DC Melles (chair) Prof Dr JE Degener Dr Ir SC de Greeff Dr T Leenstra Prof Dr JW Mouton Dr C Schultsz Dr EE Stobberingh Dr CM Verduin Members of CIb working on surveillance of antimicrobial resistance Ing J Alblas Dr Ir W Altorf-van der Kuil Dr D Frentz Dr Ir SC de Greeff Mrs A Haenen Mrs J Heereveld Mr R Hertroys Mrs M Kamst-van Agterveld Dr T Leenstra Dr A Meijer Dr NEL Meessen Drs J Monen Dr DW Notermans Dr LM Schouls Prof Dr D van Soolingen Dr EE Stobberingh Ir SHS Woudt Members of SWAB s working group on surveillance of antimicrobial use Dr S Natsch (convener) Drs C Pellicaan Dr TBY Liem Dr PD van der Linden Drs MMB Roukens Dr AW van der Velden Dr EMW van de Garde Drs M Lourens 2 NethMap 215

5 Acknowledgements We thank the Foundation for Pharmaceutical Statistics SFK, The Hague, for providing data on community usage of antimicrobial agents and all hospital pharmacists of the centres mentioned below for providing data on hospital usage. We thank Prof. Dr MC Vos, Dr R Willems, Prof Dr MJM Bonten, all participants of ISIS-AR, SERIN, GRAS, C. difficile surveillance, anaerobic pathogen surveillance, azole resistance surveillance, the Netherlands Reference laboratory for meningitis in Amsterdam, and the NIVEL for their important contributions; and the staff of the Publishing Department RIVM for preparing this report for printing. Centres contributing to the surveillance of antibiotic consumption Alkmaar, MC Alkmaar; Almelo/Hengelo, ziekenhuisgroep Twente; Almere, Flevoziekenhuis; Amersfoort, Meander MC; Amstelveen, ziekenhuis Amstelland ; Amsterdam, AMC; Amsterdam, BovenIJ ziekenhuis; Amsterdam, OLVG; Amsterdam, St.Lucas Andreas ziekenhuis; Amsterdam, VUMC; Apeldoorn, Gelre ziekenhuizen; Arnhem, Rijnstate; Assen, Wilhelmina ziekenhuis; Bergen op Zoom, Lievensberg; Boxmeer, Maasziekenhuis Pantein; Breda, Amphia ziekenhuis; Capelle a/d IJsel, IJselland ziekenhuis; Den Bosch, Jeroen Bosch ziekenhuis; Den Haag, Bronovo ziekenhuis; Den Haag, MC Haaglanden; Den Haag, HAGA ziekenhuizen; Den Helder, Gemini ziekenhuis; Deventer, Deventer ziekenhuis; Doetinchem, Slingerland ziekenhuis; Dordrecht, Albert Schweizer ziekenhuis; Ede, Gelderse vallei; Eindhoven, Catharina ziekenhuis; Emmen, Scheperziekenhuis; Gorinchem, Beatrix ziekenhuis; Gouda, Groene hart ziekenhuis; Groningen, UMCG; Haarlem, Kennemergasthuis; Haarlem, Spaarne ziekenhuis; Hardenberg, Ropcke Zweers; Harderwijk, St.Jansdal; Heerenveen, De Tjongerschans; Hoorn, Westfries gasthuis; Leiden, Diaconessenhuis; Leiden, LUMC; Leiderdorp, Rijnland ziekenhuis; Leeuwarden, Medisch centrum Leeuwarden; Lelystad, MC Zuiderzee; Maastricht, MUMC; Nieuwegein, St.Antonius ziekenhuis; Nijmegen, CWZ; Nijmegen, UMC St.Radboud; Purmerend, Waterland ziekenhuis; Roermond, Laurentius ziekenhuis; Roosendaal, Franciscus ziekenhuis; Rotterdam, Erasmus MC; Rotterdam, Maasstad ziekenhuis; Rotterdam, St.Franciscus gasthuis; Rotterdam, Ikazia ziekenhuis; Rotterdam-Dirksland, van Weel Bethesda ziekenhuis; Schiedam, Vlietland ziekenhuis; Sittard, Orbis MC; Sneek, Antonius ziekenhuis; Terneuzen, ZorgSaam; Tilburg, St. Elisabeth ziekenhuis; Tilburg, TweeSteden ziekenhuis; Tiel, Ziekenhuis Rivierenland; Utrecht, Diakonessenhuis; Utrecht, UMCU; Veghel, Ziekenhuis Bernhoven; Winterswijk, Streekziekenhuis Koningin Beatrix; Woerden, Zuwe Hofpoort; Zoetermeer, Lange Land ziekenhuis; Zutphen, Gelreziekenhuizen; Centres contributing to the surveillance of resistance to antimicrobial agents (ISIS-AR) Alkmaar, Medisch Centrum Alkmaar; Amsterdam, Slotervaartziekenhuis / Antoni van Leeuwenhoek; Apeldoorn, Gelre Ziekenhuizen; Bergen op Zoom, Lievensberg Ziekenhuis; Breda, Amphia Ziekenhuis; Delft, Microbiologisch laboratorium Reinier de Graaf Groep; Deventer, Deventer Ziekenhuis; Doetinchem, Slingeland Ziekenhuis; Dordrecht, Regionaal Laboratorium Medische Microbiologie; Ede, Ziekenhuis Gelderse Vallei; Enschede, Laboratorium voor Medische Microbiologie Twente/Achterhoek; Goes, Admiraal De Ruyter Ziekenhuis; Groningen, Laboratorium voor Infectieziekten; Haarlem, Streeklaboratorium voor de Volksgezondheid; Heerlen, Atrium Medisch Centrum Parkstad; Hilversum, Centraal Bacteriologisch en Serologisch Laboratorium; Leeuwarden, Izore, Centrum Infectieziekten Friesland; Leiden, LUMC; Nieuwegein, St. Antonius Ziekenhuis; Nijmegen, UMC St. Radboud; Nijmegen, Canisius Wilhelmina Ziekenhuis; Roosendaal, St. Franciscus ziekenhuis; Schiedam, Vlietland Ziekenhuis; NethMap 215 3

6 s-gravenhage, MC Haaglanden Westeinde; s-gravenhage, HagaZiekenhuis; s-hertogenbosch, Jeroen Bosch Ziekenhuis; Sittard-Geleen, Orbis MC; Terneuzen, Ziekenhuis ZorgSaam Zeeuws-Vlaanderen; Tilburg, Streeklab. v.d. Volksgezondheid; Utrecht, UMC Utrecht; Utrecht, Saltro; Utrecht, Diakonessenhuis; Veldhoven, Stichting PAMM; Velp, Ziekenhuis Rijnstate, loc. Velp; Woerden, Zuwe Hofpoort Ziekenhuis; Zwolle, Isala 4 NethMap 215

7 Contents Colophon 2 Acknowledgements 3 1 Introduction 7 2 Extensive summary 9 3 Use of Antimicrobials 17 Introduction Primary care Hospital care Care in nursing homes 32 4 Surveillance of resistance Methods and description of ISIS-AR data Methods Description of the ISIS-AR data Primary care ISIS-AR SERIN, Surveillance of Extramural Resistance in The Netherlands Hospital departments Outpatient departments Inpatient hospital departments (excl. ICU) Intensive Care Units Blood isolates from inpatient departments (incl. intensive care units) Urology services Respiratory pathogens Highly resistant microorganisms Carbapenem-Resistant Enterobacteriaceae Vancomycin Resistant Enterococci in Dutch hospitals Methicillin resistant Staphylococcus aureus Carbapenem-resistant Pseudomonas aeruginosa and other non-fermenters Extended spectrum Beta-lactamase producing bacteria Signaling Consultation of Hospital acquired Infections and AntiMicrobial Resistance (SO-ZI/AMR) 96 NethMap 215 5

8 4.5 Resistance in specific pathogens Neisseria meningitidis Neisseria gonorrhoeae Mycobacterium tuberculosis Resistance to influenza antiviral drugs Resistance among human anaerobic pathogens Clostridium difficile Azole resistance in Aspergillus fumigatus NethMap 215

9 1 Introduction This is NethMap 215, the SWAB/RIVM report on the use of antibiotics and trends in antimicrobial resistance in The Netherlands in 214 and previous years. NethMap is a cooperative effort of the Dutch Working Group on Antibiotic Policy (SWAB; Stichting Werkgroep Antibiotica Beleid) and the Centre for Infectious Disease Control Netherlands (CIb) at the National Institute for Public Health and the Environment (RIVM). Nethmap is issued back-to-back together with MARAN, reporting on trends in animal husbandry. In 1996, the SWAB was founded as an initiative of The Netherlands Society for Infectious Diseases, The Netherlands Society of Hospital Pharmacists and The Netherlands Society for Medical Microbiology. SWAB is fully funded by a structural grant from CIb, on behalf of the Ministry of Health, Welfare and Sports. The major aim of the SWAB is to contribute to the containment of the development of antimicrobial resistance and provide guidelines for optimal use of antibiotics, SWAB has initiated several major initiatives to achieve its goals. Among these are training programs on rational prescribing of antimicrobial drugs, development of evidence-based prescription guidelines, implementation of tailor-made hospital guides for antibiotic prophylaxis and therapy and a nationwide surveillance system for antibiotic use. CIb monitors and informs the government about potential national health threats with regard to antimicrobial resistance. Based on the national AMR surveillance system (ISIS-AR), trends in antimicrobial resistance are monitored using routine antibiotic susceptibility testing data from microbiology laboratories in the Netherlands. Furthermore, the CIb subsidizes specific surveillance programs that focus on the monitoring of specific pathogens, or even specific resistance mechanisms. Together these form the basis of the surveillance of resistance trends reported in Nethmap. NethMap 215 extends and updates the information of the annual reports since 23. Since the introduction of a more concise format last year, reflected in both a different format as well as more concise information we have tried to further improve and highlight the most important trends. The reader is encouraged to visit for tailored overviews of resistance development. NethMap 215 7

10 Lately, the appearance of highly resistant microorganisms (HRMO s) has received significant attention and has become a significant public health issue. The epidemiological background of these microorganisms is increasingly complex, as are the challenges to antimicrobial treatment. We therefore provide in a separate chapter a comprehensive overview covering the major trends in antimicrobial resistance, consequences for therapeutic choices and these may serve as a basis for public health policies. NethMap parallels the monitoring system of antimicrobial resistance and antibiotic usage in animals in The Netherlands, entitled MARAN Monitoring of Antimicrobial Resistance and Antibiotic Usage in Animals in The Netherlands. Jointly, NethMap and MARAN provide a comprehensive overview of antibiotic usage and resistance trends in The Netherlands in humans and in animal husbandry and therefore offer insight into the ecological pressure associated with emerging resistance. We believe NethMap/Maran continues to contribute to our knowledge and awareness regarding the use of antibiotics and the resistance problems that are present and may arise in the future. We especially thank all those who are contributing to the surveillance efforts, and express our hope that they are willing to continue their important clinical and scientific support to NethMap/Maran and thereby contribute to the general benefit and health of the people. The editors: Dr Ir SC de Greeff Prof Dr JW Mouton 8 NethMap 215

11 2 Extensive summary In the Netherlands, several surveillance programs have been developed over the years to monitor antimicrobial resistance in important pathogens in different settings. In addition, a number of specific surveillance programs exist that focus on the monitoring of specific pathogens, or even specific resistance mechanisms. These programs often include susceptibility testing, including conformation of important resistance mechanisms and molecular typing. For instance, all MRSA isolates cultured in the Netherlands are submitted to a reference laboratory for further analysis. In table 2.1 an overview is provided of surveillance programs that are included in Nethmap Most important trends in antimicrobial use In GPs Antibiotic use declined for the third successive year from DDD/1 inhabitants per day in 211 to 1.54 DDD/1 inhabitants per day in 214. The use of azithromycin increased whereas the use clarithromycin declined further. There was a 13% increase in use of ciprofloxacin which may be related to the decrease in the use of norfloxacin and levofloxacin; overall quinolone use increased 3%. In nursing homes The mean use based on 34 nursing homes was 65 DDD/1 residents/day but varied widely between 14 and 165 DDD/1 residents/day. The most frequently used antibiotics are combinations of penicillins (mainly amoxicillin with clavulanic acid), with 18.9 DDD/1 residents/day, nitrofurantoin derivates (13.7 DDD/1 residents/day) and fluoroquinolones (7.9 DDD/1 residents/day). NethMap 215 9

12 Table 2.1 Overview of Surveillance programs in the Netherlands. Surveillance program 1 Origin of isolates availability Sources 214 Central or decentral susceptibility testing Surveillance program aimed at resistance surveillance in major pathogens SERIN GP GP practices from NIVEL ISIS-AR GP, Hospital, Nursing homes Specific surveillance program aimed at resistance surveillance in specific pathogens Central testing Microdilution Method of susceptibility testing laboratories Decentral testing Various methods used in routine susceptibility testing Neisseria meningitidis Hospital Nationwide Central testing E-test Neisseria gonorrhoeae STI centers 26-89% (of STI center attendees) Decentral testing E-test Mycobacterium tuberculosis General population Nationwide Primarily central testing Influenza antiviral drugs community, GP, nursing home, hospital Resistance among anaerobic pathogens Clostridium difficile Hospital, nursing homes Azole resistance in Aspergillus fumigatus 25- NIVEL GP sentinels, SNIV nursing home sentinels, hospital/ regional laboratories central testing (RIVM, NIC- ErasmusMC, WHO- CC London) Hospital 21-1 lab Central testing E-test Agar dilution and BACTEC-Mgit 96 (liquid breakpoint) Neuraminidase enzym inhibition assay; for established molecular markers sequencing and/or single nucleotide polymorphism (SNP) PCR hospitals (de)central testing E-test and ribotyping Hospital University hospitals Central testing EUCAST methodology 1 SERIN = Surveillance of Extramural Resistance in The Netherlands; ISIS-AR = Infectious Disease Surveillance Information System on Antibiotic Reistance GP = General practitioner; NIVEL = Netherlands institute for health services research; SNIV = National sentinel surveillance network for infectious diseases in nursing homes; STI = Sexually transmitted Infections; WHO-CC = World Health Organisation Collaborating Centre 1 NethMap 215

13 In hospitals The in-patient use of antibiotics in 213 increased from 71.3 DDD/1 patient days in 212 to 74.7 DDD/1 patient days in 213. Antibiotic use per 1 admissions was 37.8 DDD/1 admissions which is higher than in 212 (295.7 DDD/1 admissions) but comparable to 211 (36.4 DDD/1 admissions in 211). After a peak in total use of 1.61 DDD/1 inhabitants/day in 21, this value decreased further in 213 to.951 DDD/1 inhabitants/day. Carbapenem use, especially meropenem, was again slightly increased, although, in a European context, it s use is still low. University hospitals account for most of the meropenem use. The point prevalence study in 51 hospitals (twice as many as 213) by the PREZIES network showed that 32% of all admitted patients (N=12,329 patients) received antibiotics, the same figure as last year and the year before. Most often used antibiotics were amoxicillin with clavulanic acid (18%), ciprofloxacin (11%) and cefuroxim (8%). 2.2 Most important trends in antimicrobial resistance In GPs For most antimicrobials, there are no significant shifts in resistance levels since 21. The exceptions are nitrofurantoin, with slowly rising levels up to 3% in E. coli and trimethoprim and co-trimoxazol that show a decrease in resistance, although still between 2-3% for most species. There appears an increase in resistance to fosfomycin and amoxicillin with clavulanic acid in some species. A distinction was made for patients aged below and above 12 years of age. In general, resistance rates in the older age group were slightly higher than in the younger age group. The percentage of highly resistant microorganisms (HRMO) and multi-drug resistance remained relatively low (< 4%) in all Enterobacteriaceae. The Gonococcal Resistance to Antimicrobials Surveillance (GRAS) reported no resistance to ceftriaxone and spectinomycin found. In hospitals Compared to 21, overall resistance rates for many antimicrobials were similar or slightly lower. The major exception was nitrofurantoin, which is, similar to GP, slightly increasing and 4% in outpatient departments for E. coli. A similar trend is observed for fosfomycin and amoxicillin with clavulanic acid in some species. The percentage of HRMO was highest among K. pneumoniae i.e. 8% (excl. ICU departments) and 11% (ICU). Carbapenem resistance in P. aeruginosa increased from 2% to 4% (excl ICU). CRE were a rare occurrence in the Netherlands;.1% of E. coli and.15% of K. pneumoniae were non-susceptible to carbapenems. OXA-48 was the most prevalent carbapenemase detected. The prevalence of MRSA remains low. Resistance to vancomycin remained rare in enterococci (<.5%). Resistance to penicillin (<.5%) in pneumococci was still rare in the Netherlands. Resistance to penicillin in N. meningitidis was not found in 214. For C. difficile, the prevalence of ribotype 27 was stable at 3% and no indications for clinical relevant resistance to metronidazole, vancomycin, and fidaxomicin. The overall frequency of azole resistance in A. fumigatus in 214 was 7.2% compared to 7.8% in 213. NethMap

14 2.3 Antibiotic use and resistance in the veterinary sector In 214 the sales of antimicrobial veterinary medicinal products (27 tonnes) decreased by 4.4%, compared to 213 (217 tonnes). The total sales decreased from 29, the index year as defined by the Ministry of Economic Affairs, to 214 by 58.1%. The policy objective for 215, a 7% reduction compared to 29, will therefore be a challenge. Compared to 27, the year with highest sales (565 tonnes), the decrease in sales is 63%. In most livestock sectors reductions in antibiotic use levelled off in comparison with 213, except for poultry and dairy cattle. In poultry antibiotic use increased again in 214, probably as a result of changes in prescription patterns. In dairy cattle a substantial reduction in use was noted and a shift in antibiotic use from 3rd and 2nd choice to 1st choice antibiotics, particularly in dry cow treatment. Resistance levels in S. Typhimurium isolates from human samples have increased over the years until 21 after which a constant tendency to decrease was observed until 213. In 214 resistance levels for almost all antimicrobials tested stabilized. In 214 the resistance rates seem to have stabilized in C. jejuni from broilers and poultry meat. Ciprofloxacin resistance was at a high level and still rising in Campylobacter spp. causing infections in human patients ( >6%). However, resistance to erythromycin, macrolides being the first choice antibiotic in human infections, was still low. For Campylobacter from human patients, resistance levels were higher for travel related infections compared to domestically acquired campylobacteriosis. Over the last decade, Shigella Toxin producing E. coli (STEC) isolates show a tendency of increasing resistance to ampicillin, tetracycline, sulfamethoxazole and trimethoprim. Resistance to the quinolones (ciprofloxacin and nalidixic acid) decreased in 214. As in the former four years, no ESBL-producing isolates were detected In most animal species the resistance levels of indicator E. coli from fecal samples stabilized in 214. This may reflect the use patterns of antibiotics in the different livestock species. In isolates from broiler meat, beef and pork, resistance showed a tendency to decrease. The decrease in cefotaxime resistant E. coli from , has levelled off in 214. The prevalence of livestock being positive for ESBL/AmpC producing E. coli in the faeces was 67% in broilers, 34% in laying hens, 18% in slaughter pigs, 23% in white veal calves, 14% in rosé veal calves and 9% in dairy cows. Poultry meat was most frequently contaminated (67%), which was slightly lower than found in former years (83% in 213 and 73% in 212). The dominant human ESBL-gene (bla CTX-M-15 ) was more frequently found in animals or their products. This is an unwanted development that warrants extra attention in the surveillance in food-animal sources. In 214 in 161 fecal samples from broilers, veal calves, slaughter pigs and dairy cows no carbapenemase-producing Enterobacteriaceae were detected. These findings indicate that reductions in the total quantity of antibiotics used in the Netherlands and in 3rd and 4th generation cephalosporins are associated with a reduction of the general levels of antimicrobial resistance and the levels of ESBLs. These associations are indicative of a direct causal association between usage of antibiotics and antimicrobial resistance. This view is supported by the current levelling off in antibiotic use directly followed by a stabilization of resistance levels. This may warrant a re-evaluation of the current targets for antibiotic use in relation to targets for antimicrobial resistance in animals and food thereof. 12 NethMap 215

15 2.4 Implications for therapy Overall, with a few exceptions, no major shifts in resistance rates have occurred in The Netherlands over the last five years. The resistance rates in 214 did not increase further for most antibiotics. Yet, there is a continuing concern. For some microorganisms where resistance rates are apparently similar over the last years, a MIC creep is observed since last year below the clinical breakpoint, indicating that resistance may appear in the coming years. Although resistance has not increased further, empiric (mono) therapy for some of these agents is now unjustified in the severely ill patient for many of the antibiotics that were long considered as first line of treatment. Routine culturing with antibiograms remains mandatory to tailor therapy to the individual patient. If broad spectrum therapy is initially chosen, antibiograms should be used to narrow down antimicrobial therapy to prevent even further emergence of resistance and culture repeated if indicated. It should be realized that the resistance rates reported are for one isolate per patient, and only the first one, and that resistance in the individual patient, especially those that stay longer in the hospital, is significantly higher than reported here. In the summary below, some of the most important implications for therapy are provided, based on the general trends of resistance. As implications differ by category of patient and indication of use, the summary is organized as such. It should be borne in mind that the majority of conclusions below are based on agents used as intravenous therapy, except for agents that are available as oral drugs only or have a specific indication such as UTI. Non-susceptible rates can be higher than resistance rates in some cases. In GPs Urinary tract infections Approximately 8% of Gram-negatives cultured were E. coli, K. pneumoniae and P. mirabilis. High levels of resistance to amoxicillin, trimethoprim and co-trimoxazole make these agents less suitable for empirical treatment in UTI both in children and adults. However, resistance to trimethoprim and co-trimoxazole has been decreasing for several years and is increasingly an option. The best suitable treatment options for uncomplicated UTI are still nitrofurantoin (3% resistance in E. coli, and slowly increasing) and fosfomycin (1% resistance in E. coli, but >3% in K. pneumoniae). Resistance to amoxicillin with clavulanic acid was > 1% in Enterobactereaceae indicating that care should be taken with empirical treatment without further diagnostic work-up. The results indicate sampling for antimicrobial susceptibility testing becomes increasingly important in the treatment of UTI. In hospitals Outpatient departments Except for nitrofurantoin and fosfomycin, high levels of resistance preclude empirical treatment with oral agents for UTI; culture and tailored therapy are necessary. Resistance rates in the three major species are comparable to, or slightly higher than in GP patients, thus the treatment strategies will be largely similar for these species The species distribution in UTI in outpatient departments is significantly different from that of GP s reflecting more complicated patients. The resistance rates differ significantly by species and cultures are required for tailored therapy. NethMap

16 Unselected hospital patient departments High levels of resistance to amoxicillin, amoxicillin with clavulanic acid, cefuroxime, co-trimoxazole and ciprofloxacin, make these agents less suitable for empirical treatment in serious infections. The ciprofloxacin resistance rate of 17% in E.coli has further increased and is especially worrisome. Piperacillin/tazobatam, cefotaxime/ceftriaxone, ceftazidime and aminoglycoside resistance rates are all between 5 and 1% and in the range that is generally considered to be acceptable for patients not severely ill. Combination therapy of a beta-lactam with an aminoglycoside are still the best suitable options for empirical treatment in serious infections. Intensive care patients There are no significantly important shifts in 214. High levels of resistance to amoxicillin, amoxicillin with clavulanic acid, cefuroxime, co-trimoxazole and ciprofloxacin, make these agents less suitable for empirical treatment in serious infections. The ciprofloxacin resistance rate of 13% in E.coli is similar to 213. There are significant differences in resistance rates between hospitals as well as over time. This clearly indicates that empiric therapy should be based on the local epidemiology of resistance. Piperacillin/tazobactam, cefotaxime/ceftriaxone, ceftazidime and aminoglycoside resistance rates are all between 5 and 1%. This is in a range that warrants combination therapy or at least close monitoring for the severely ill. However, resistance to combinations of a beta-lactam and an aminoglycoside is between 1 and 5%. It should be realized however, that resistance to combinations is based on the effect of the drug alone and does not take into account any synergistic effects that may be present. 2.5 Implications for public health and health policy Antibiotic resistance is a serious threat to public health in Europe, leading to increased healthcare costs, prolonged hospital stays, treatment failures and sometimes death. At the European level there has been a significant increasing trend in the percentages of K. pneumoniae resistant to fluoroquinolones, third-generation cephalosporins and aminoglycosides, as well as combined resistance to all three antibiotic groups over the last years. During the same period, resistance to third-generation cephalosporins increased significantly. The most worrying however, is the increase in the percentage of carbapenem resistance in K. pneumoniae which causes serious concern and a threat to patient safety in Europe. In the Netherlands, with a few exceptions, no major shifts in resistance rates have occurred over the last five years. The resistance rates in 214 did not increase further for most antibiotics. Yet, there is a continuing concern. For some microorganisms where resistance rates are apparently similar over the last years, an MIC creep is observed since last year below the clinical breakpoint, indicating that resistance may appear in the coming years. The current measures to control the increase in antimicrobial resistance follow the perspective of human medicine: prudent antibiotic use, and screening and isolation of (hospitalised) patients at-risk. 14 NethMap 215

17 However, introductions of resistant bacteria from abroad, from livestock, from the environment and from the general population play a role in the spread of resistance. Consequently, a much wider variety of control measures to reduce the population at risk is needed. To take adequate interventions to control this spread, harmonized and integrated surveillance at regional, local and national level, in human healthcare as well as in the open population, the environment, food-producing animals and the food chain, is needed. To achieve this, intensive collaboration between professionals in the private and public domain in both human and veterinary health care will be necessary. Conclusions The data presented in NethMap 215 demonstrate that the continuing shifts in patterns of antibiotic use and resistance require a rethinking of antimicrobial use and policy, including restricted use of some classes of antibiotics, in particular those that are employed as a last line of defense. To control the increase and spread of antibiotic resistance, trends in resistance and antibiotic use should be carefully monitored to allow intervention if necessary. NethMap

18 16 NethMap 215

19 3 Use of Antimicrobials Introduction In this chapter the use of antimicrobials over the past decade is reported. First, extramural antibiotic use from 25 until 214 is presented, including total antibiotic use, as well as use of subgroups and individual antibiotics. Second, antibiotic use in hospital care from 24 until 213 is reported using several measures: DDD/1 patient days, DDD/1 admissions, as well as in DDD/1 inhabitant days (DID). Third, antibiotic use data from the point prevalence study of the PREZIES network are reported. Finally, we report data of antibiotic use in nursing homes in the Netherlands. For the first time, we present also point prevalence data on antibiotic use in nursing homes, collected by PREZIES. 3.1 Primary care Methods Dutch data of outpatient antibiotic use are annually obtained from the SFK (Foundation for Pharmaceutical Statistics, the Hague) and are expressed in numbers of Defined Daily Doses (DDD) for each ATC-5 code. The SFK collects data from 9% of the Dutch community pharmacies (serving 91.5% of the Dutch population) and extrapolates the data to 1%. Data are presented as DDD per 1 inhabitants per day (DID). Results Compared to 213, total community antibiotic use in 214 showed a small decrease of.27 DID to 1.54 DID. After years of increases in antibiotic use from 1.51 in 25 to DID in 211, total use declined for the third successive year (Table 3.1). Broken down by groups of antibiotics, decreases were seen for the use of amoxicillin with clavulanic acid (8% to 1.55 DID), for macrolides (4% to 1.22 DID), for amoxicillin and for tetracyclines (mainly doxycycline). Of the macrolides, use of azithromycin increased to.73 DID, whereas the use of NethMap

20 Table 3.1 Ten years data on the use of antibiotics for systemic use (J1) in primary care (DDD/1 inhabitant-days), (Source: SFK). ATC Group* Therapeutic group J1AA Tetracyclines J1CA J1CE J1CF J1CR Penicillins with extended spectrum Beta-lactamase sensitive penicillins Beta-lactamase resistant penicillins Penicillins + betalactamase-inhibitors J1D Cephalosporins J1EA J1EC Trimethoprim and derivatives Intermediate-acting sulphonamides J1EE Sulphonamides + trimethoprim J1FA Macrolides J1FF Lincosamides J1GB Aminoglycosides J1MA Fluoroquinolones J1MB Other quinolones J1XB Polymyxins J1XE Nitrofuran derivatives J1XX5 Methenamine J1 Antibiotics for systemic use (total) * From the 213 edition of the Anatomical Therapeutic Chemical (ATC) classification system clarithromycin further declined to.38 DID. Use of ciprofloxacin increased by 13% compared to 213. Use of nitrofurantoin is still increasing in the Netherlands. Discussion The positive news is that after years of increase in antibiotic use until 211, now for the third year a slight decrease was seen in overall use of antibiotics in the Dutch community. Nevertheless, it has to be mentioned that use of three specific antibiotics increased: azithromycin, ciprofloxacin and nitrofurantoin. For azithromycin, this is partly due to shifts in specific antibiotics used within the subgroup of macrolides, but the 13% increase in use of ciprofloxacin needs further assessment. Also of interest is the steadily increasing use of nitrofurantoin. 18 NethMap 215

21 Figure 3.1 a-d Use of antibiotics for systemic use in primary health care, (Source:SFK). DDD/1 inhabitant-days amoxicillin (J1CA4) co-amoxiclav (J1CR2) DDD/1 inhabitant-days erythromycin (J1FA1) azithromycin (J1FA1) clarithromycin (J1FA9) DDD/1 inhabitant-days.6.5.4, ofloxacin (J1MA1) levofloxacin (J1MA12) ciprofloxacin ((J1MA2) moxifloxacin ((J1MA14) norfloxacin (J1MA6) DDD/1 inhabitant-days Trimethoprim (J1EA1) Nitrofurantoine (J1XE1) Sulphametoxazole with trimethoprim (J1EE1) NethMap

22 3.2 Hospital care Methods Data on the use of antibiotics in Dutch hospitals were collected by means of a questionnaire distributed to all Dutch hospital pharmacists. Data were received from 68 out of 91 hospitals, together with the annual number of bed-days and admissions. Data were entered in the ABC-calculator ( for conversion into DDDs, using the ATC/DDD classification from the WHO 1. Use of antibiotics is expressed as DDD/1 patient-days and in DDD/1 admissions. The number of patient-days is calculated by subtracting the number of admissions from the number of bed-days to compensate for the fact that in bed-days statistics both the day of admission and the day of discharge are counted as full days. Hospital extrapolated data, expressed in DDD/1 inhabitants per day, as used for the international antibiotic surveillance of the ECDC, are also reported. Hospital consumption data and corresponding hospital statistics were used to estimate total hospital consumption in the Netherlands. Methods are further described in Kwint et al 2.Data on annual number of inhabitants in the Netherlands were obtained from Statistics Netherlands (CBS). Dutch hospitals furthermore collected detailed data on antibiotic usage (according to the methodology proposed by the ECDC), combined with the PREZIES prevalence study on healthcare associated infections. All patients admitted to the hospital had to be included, with the exception of patients on psychiatric wards and in the haemodialysis centre. Only systemic antibacterials (ATC-code J1) were included, with a maximum of three concomitant substances per patient. Results Compared to 212, the in-patient use of antibiotics in 213 increased from 71.3 DDD/1 patient-days to 74.7 DDD/1 patient-days (Table 3.2). From 24 to 29, there was a steady increase in total use from 52 to about 71 DDD/1 patient-days. Between 29 and 212, use remained about stable around 71 DDD/1 patient-days. Antibiotic use per 1 admissions also increased to 37.8 DDD/1 admissions, after years of declines to a minimum of DDD/1 admissions in 212. Broken down by hospital category, university hospitals used the least antibiotics (72.5 DDD/1 patient-days), whereas large teaching hospitals the most (76. DDD/1 patient-days). General hospitals used 74.8 DDD/1 patient-days on average. With respect to the ATC-4 level figure 3.2 shows the distribution of use per antibiotic subgroup for these different types of hospitals in 213. Notable is the large difference in the relative use of combinations of penicillins (mainly amoxicillin with clavulanic acid) between university hospitals (15.2%), large teaching hospitals (17.9%) and general hospitals (24.%). Most carbapenems and glycopeptides were used in university hospitals and relatively more nitrofuran derivates in general hospitals. Large teaching hospitals were the highest users of cephalosporins. The increase in antibiotic use in 213 is mainly due to a substantial increase in the use of cephalosporins (Fig. 3.3 and 3.4), with an increase, compared with 212, of 2.% for first-generation (cefalexin, cefalotin and cefazolin were used). A higher increase was seen on second- and third-generation cephalosporins 2 NethMap 215

23 Table 3.2 Ten years use of antibiotics for systemic use (J1) in hospitals, (Source: SWAB). ATC Group* Therapeutic group J1AA Tetracyclines J1CA Penicillins with extended spectrum J1CE Beta-lactamase sensitive penicillins J1CF Beta-lactamase resistant penicillins J1CR Combinations of penicillins, incl. beta-lactamaseinhibitors J1DB Cephalosporins DE J1DF Monobactams J1DH Carbapenems J1EA Trimethoprim and derivatives J1EC Intermediate-acting sulfonamides J1EE Combinations of sulfonamides and trimethoprim, including derivatives J1FA Macrolides J1FF Lincosamides J1GB Aminoglycosides J1MA Fluoroquinolones J1MB Other quinolones J1XA Glycopeptides J1XB Polymyxins J1XC Steroid antibacterials (fusidic acid) J1XD Imidazole derivatives J1XE Nitrofuran derivatives J1XX5 Methenamine J1XX8 Linezolid J1 Antibiotics for systemic use (total) expressed in DDD/1 patiënt days J1 Antibiotics for systemic use (total) expressed in DDD/1 admissions * From the 213 edition of the Anatomical Therapeutic Chemical (ATC) classification system NethMap

24 Figure 3.2 Distribution (%) of the use of antibiotics for systemic use (J1) in hospitals, 213 (Source:SWAB) 1% other antibacterials Nitrofuran derivatives 9% Imidazole derivatives Steroid antibacterials (fusidic acid) 8% Polymyxins Glycopeptides 7% Other quinolones Fluoroquinolones 6% 5% 4% Aminoglycosides Lincosamides Macrolides Combinations of sulfonamides and trimethoprim, including derivatives Intermediate-acting sulfonamides Trimethoprim and derivatives Carbapenems 3% Monobactams Cephalosporins 2% 1% Combinations of penicillins, incl. beta-lactamase-inhibitors Beta-lactamase resistant penicillins Beta-lactamase sensitive penicillins Penicillins with extended spectrum % total N=68 university hospitals N=8 large teaching hospitals N=18 general hospitals N=42 Tetracyclines respectively 14.7% for second- and 15.3% for third-generation cephalosporins when measured in DDD/1 patient days. Use of second-generation cephalosporins consisted of: cefoxitin, cefuroxime, cefamandole and cefaclor, third-generation cephalosporins included use of: cefotaxime, ceftazidime, 22 NethMap 215

25 Figure 3.3 Use of beta-lactams in hospitals, expressed as DDD/1 patient-days (A) and DDD/1 admissions (B), (Source:SWAB). A B DDD/1 patient-days DDD/1 admissions ampicillin (J1CA1 ) amoxicillin (J1CA4) benzylpenicillin (J1CE1) flucloxacillin (J1CF5) co-amoxiclav (J1CR2) piperacillin-tazobactam (J1CR5) DDD/1 patient-days First-generation cephalosporins (J1DB) Third-generation cephalosporins (J1DD) DDD/1 admissions Second-generation cephalosporins (J1DC) Fourth-generation cephalosporins (J1DE) DDD/1 patient-days Meropenem (J1DH2) Ertrapenem (J1DH3) Doripenem (J1DH4) Imipenem/cilastatin (J1DH51) DDD/1 admissions ceftriaxone, cefixime and ceftibuten. University hospitals use much more third-generation cephalosporins than first- and second-generation ones, while in general hospitals, the use is evenly distributed among the three categories of cephalosporins (figure 3.5). However, in large teaching hospitals, use of second generation cephalosporins is increasing, while the first and third generation ones are decreasing. Besides the cephalosporins there are some other antimicrobials with an increased use in 213. Flucloxacillin shows a substantial increase to 7.9 DDD/1 patient-days. Meropenem use further NethMap

26 Figure 3.4 Use of macrolides, aminoglycoside, fluoroquinolones and glycopeptides in hospitals, expressed as DDD/1 patient-days (A) and DDD/1 admissions (B), (Source:SWAB). DDD/1 patient-days A Erythromycin (J1FA1) Roxithromycin (J1FA6) Azithromycin (J1FA1) Clarithromycin (J1FA9) DDD/1 admissions B DDD/1 patient-days A B Tobramycin (J1GB1) Gentamicin parenteral (J1GB3) Gentamicin local (J1GB3) Amikacin (J1GB6) DDD/1 admissions DDD/1 patient-days A Ofloxacin (J1MA1) Ciprofloxacin (J1MA2) Norfloxacin (J1MA6) Levofloxacin (J1MA12) Moxifloxacin (J1MA14) DDD/1 admissions B DDD/1 patient-days A B Vancomycin (J1XA1) Teicoplanin (J1XA2) DDD/1 admissions 24 NethMap 215

27 Table 3.3 Ten years data on the use of antibiotics for systemic use (J1) in hospital care (DDD/1 inhabitant-days), (Source: SWAB). ATC Group Therapeutic group J1AA Tetracyclines J1CA J1CE J1CF J1CR Penicillins + betalactamase-inhibitors J1DB- DE Penicillins with extended spectrum Beta-lactamase sensitive penicillins Beta-lactamase resistant penicillins Cephalosporins J1DF Monobactams J1DH Carbapenems J1EA J1EC Trimethoprim and derivatives Intermediate-acting sulphonamides J1EE Sulphonamides + trimethoprim J1FA Macrolides J1FF Lincosamides J1GB Aminoglycosides J1MA Fluoroquinolones J1MB Other quinolones J1XB Polymyxins J1XE Nitrofuran derivatives J1XX5 Methenamine J1XX8 Linezolid J1 other antibiotics Antibiotics for systemic use (total) increased to 1.5 DDD/1 patient-days in 213. University hospitals account for most of the meropenem use with 2.9 DDD/1 patient-days compared to 1.1 and 1. DDD/1 patient-days in large teaching and general hospitals respectively (figure 3.5). Finally use of aminoglycosides as well as glycopeptides overall showed a small increase in 213. Large teaching and general hospitals show a higher use of gentamicin than university hospitals (figure 3.5), whereas glycopeptides were preferably used in university hospitals with 2.6 DDD/1 patient-days, compared to about 1 DDD/1 patient-days in large teaching and general hospitals. NethMap

28 Figure 3.5 Use of cephalosporins (A), carbapenems (B), aminoglycosides (C), glycopeptides (D) and fluoroquinolones (E) in hospitals broken down by type of hospital, expressed as DDD/1 patient-days, (Source: SWAB) A DDD/1 patient-days University hospitals DDD/1 patient-days General hospitals DDD/1 patient-days Large teaching hospitals First-generation cephalosporins (J1DB) Second-generation cephalosporins (J1DC) Third-generation cephalosporins (J1DD) Fourth-generation cephalosporins (J1DE) B DDD/1 patient-days DDD/1 patient-days University hospitals Large teaching hospitals DDD/1 patient-days General hospitals Meropenem (J1DH2) Ertrapenem (J1DH3) Doripenem (J1DH4) Imipenem/cilastatin (J1DH51) 26 NethMap 215

29 Figure 3.5 (continued) Use of cephalosporins (A), carbapenems (B), aminoglycosides (C), glycopeptides (D) and fluoroquinolones (E) in hospitals broken down by type of hospital, expressed as DDD/1 patient-days, (Source: SWAB) C DDD/1 patient-days University hospitals DDD/1 patient-days General hospitals DDD/1 patient-days Large teaching hospitals Tobramycin (J1GB1) Gentamicin (J1GB3) Amikacin (J1GB6) D DDD/1 patient-days DDD/1 patient-days University hospitals large teaching hospitals DDD/1 patient-days General hospitals Vancomycin (J1XA1) Teicoplanin (J1XA2) NethMap

30 Figure 3.5 (continued) Use of cephalosporins (A), carbapenems (B), aminoglycosides (C), glycopeptides (D) and fluoroquinolones (E) in hospitals broken down by type of hospital, expressed as DDD/1 patient-days, (Source: SWAB) E DDD/1 patient-days DDD/1 patient-days University hospitals Large teaching hospitals DDD/1 patient-days General hospitals Ofloxacin (J1MA1) Ciprofloxacin (J1MA2) Norfloxacin (J1MA6) Levofloxacin (J1MA12) Moxifloxacin (J1MA14) A decrease in use in 213 is seen for ciprofloxacin use, which decreased further by 1.8% compared to 212, as well as the use of amoxicillin with clavulanic acid which declines from 14.1 in 212 to 13.8 DDD/1 patient-days in 213. Over 75% of the antimycotics (J2), antimycobacterials (J4) and antivirals (J5) for systemic use were used in university hospitals. In table 3.4 use of J2, J4 and J5 in university hospitals is presented from 27 until 213, expressed in DDD/1 patient-days. The use of antimycotics increased in 213 compared to 212, mainly because of an increased use of amfothericin B. Use of antimycobacterials increased to 2.88 DDD/1 patient-days, caused by an increased use of rifampicin. Use of antivirals remained stable at 5.47 DDD/1 patient-days in 213. In 214 PREZIES data were received from fifty one hospitals (twice as much as in 213), including patients of which 3988 received antibiotics, with a total of 532 prescriptions (276 for community acquired infections, 681 for nosocomial infections, 674 for medical prophylaxis, 53 for surgical prophylaxis and 547 for other or unknown indications). Antibiotic use for these indications is depicted in figure 3.6. Most often used antibiotics were amoxicillin with clavulanic acid (18%), ciprofloxacin (11%) and cefuroxim (8%). Cefazolin was used in 54% cases of surgical prophylaxis. Use for medical prophylaxis was more diverse, ciprofloxacin was most often used (13%), followed by amoxicillin with clavulanic acid and trimethoprim/sulfamethoxazole. 28 NethMap 215

31 Table 3.4 Use of antimycotics, antimycobacterials and antivirals for systemic use (J2, J4, J5) in university hospitals (DDD/1 patient-days), (Source: SWAB). ATC Group * Therapeutic group J2AA1 Antibiotics (amphotericin B) J2AB2 Imidazole derivatives (ketoconazole) J2AC Triazole derivatives J2AX Other antimycotics for systemic use J2 Antimycotics for systemic use (total) J4AA Aminosalicylic acid and derivatives J4AB Antibiotics (mainly rifampicin) J4AC Hydrazides (mainly isoniazide) J4AD Thiocarbamide derivatives J4AK Other drugs for treatment of tuberculosis (pyrazinamide, ethambutol) J4AM Combinations of drugs for tuberculosis J4BA Drug for treatment of leprosy (dapson) J4 Antimycobacterials for systemic use (total) J5AB Nucleosides excl. Reverse transcriptase inhibitors (J5AB) J5AD Phosphonic acid derivatives (J5AD) J5AE Protease inhibitors (J5AE) J5AF J5AG Nucleoside reverse transcriptase inhibitors (J5AF) Non-nucleoside reverse transcriptase inhibitors (J5AG) J5AH Neuraminidase inhibitors (J5AH).2.5 n.a.# J5AR Antivirals for the treatment of HIV, combinations (J5AR) J5AX Other antivirals (J5AX) J5 Antivirals for systemic use (total) * From the 213 edition of the Anatomical Therapeutic Chemical (ATC) classification system # Total use not to be assesed because of alternative distribution during the pandemic Discussion Compared with 212 we seen an intensification of antibiotic use in hospitals and in individual patients, as antibiotics use increased by almost 5% when measured in DDD/1 patient-days and 4% when expressed in DDD/1 admissions. There are marked shifts between different subgroups of antibiotics. Increased use of 3rd-generationcephalosporins and meropenem is of particular interest, even though, in a European context, it s use is still low. As illustrated in the results there are marked differences between the three types of hospitals. Most remarkable is the difference in use of the cephalosporins. University hospitals have a higher use NethMap